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| Date: 08-15-2016 | HC# 011642-550 |
Durham SH, Stamm PL, Eiland LS. Cranberry
products for the prophylaxis of urinary tract infections in pediatric patients.
Ann Pharmacother. December
2015;49(12):1349-1356.
Cranberry (Vaccinium spp., Ericaceae) products have been shown to be effective
in preventing recurrent urinary tract infections (UTIs) in women, 30% of whom
experience a UTI in their lifetime, compared with 1% of men.* Once thought to
acidify the urinary tract (studies show pH does not actually change), it is now
thought that cranberry compounds, specifically A-type proanthocyanidins (PACs),
inhibit P-fimbriated Escherichia coli bacteria
from binding to epithelial walls. E. coli
causes 90% of initial UTIs and 75% of recurring infections; more than 90% of
nephritogenic E. coli have P
fimbriae. Also, cranberry is thought to inhibit biofilm formation. Cranberry
products do not disrupt gastric flora or promote bacterial resistance; in
addition, they are easy to obtain and use.
UTIs are common in the pediatric population,
with 8% of girls and 2% of boys diagnosed with a UTI by age 11. Up to 35% of
patients have recurrent UTIs that may have long-term effects. UTI risk factors
include obstruction to urinary flow and urinary stasis; the latter can be
caused by vesicoureteral reflux (VUR), anatomical abnormalities, neuropathic
bladder, or indwelling catheters. Besides E.
coli, UTIs in children are often caused by Pseudomonas spp., especially in children with neurogenic bladder,
frequent instrumentation, or indwelling catheters. Prophylactic low-dose
antibiotics may be used in children with obstructive disease or VUR to lower
risks of recurrent UTIs, but international trials report conflicting results
for the practice. A 2011 Cochrane review concluded that prophylaxis reduced
risks of recurrence but found the benefit small compared to risks. Several
studies report that use of antibiotic prophylaxis leads to bacterial resistance.
With a need for new strategies for treating UTIs in children, researchers have
studied cranberry's beneficial effects. The authors searched PubMed database entries
spanning 1966 to June 2015, identifying eight relevant randomized controlled
trials (RCTs).
Three RCTs involving otherwise healthy
children used cranberry juice as their active intervention; however, they
varied by the following: sample size; whether or not the UTI was caused exclusively
by E. coli; whether or not they included
children with VUR, and, if so, what grade VUR; whether they included females
only or both sexes; and the products used. Only one study used cranberry juices
with known PAC percentages (37% in the active arm, 0% in the control arm). Despite
these and other differences in design and procedures, all three studies found
benefits for cranberry juice over placebo, no intervention, or Lactobacillus spp. drink; two reported
significant risk reductions for UTIs.
In children with anatomical abnormalities, five
RCTs had mixed results as follows:
(1) A randomized, single-blind, crossover
trial treated 40 children with neuropathic bladders, but only 21 (52.5%)
completed the study; 12 dropped out because of the taste, cost, and/or caloric
content of the cranberry juice used. On study completion, there were no
significant differences in UTI incidence between groups (P = 0.5566), or in the
subset receiving prophylactic antibiotics (P = 0.2845).
(2) In a double-blind, crossover RCT assessing
effects of cranberry prophylaxis on neurogenic bladder due to myelomeningocele
and clean intermittent catheterization, 15 children received either cranberry
concentrate or placebo for 12 weeks, then crossed over for an additional 12
weeks. They were followed for six months, with no difference found in the percentage
of urine cultures testing positive for a UTI pathogen in the groups at the end
of the study. Researchers theorized that the voiding difficulty caused by
neurogenic bladder may have overwhelmed effects of the cranberry product. They
further hypothesized that patients with urogenital abnormalities or chronic
medical conditions may have UTIs caused by
E. coli that do not express adhesins and would thus not benefit from
cranberries.
(3) Another crossover RCT in a similar
population as the second study included 20 patients. After a year, significant
reductions were seen in UTI rates in the cranberry arm (P = 0.012), in females
(P = 0.008), in patients without VUR (P = 0.029), and in patients with renal
scarring (P = 0.033). In addition, 16 patients experienced pyuria during the
placebo arm, whereas only two experienced this during the cranberry arm (P =
0.000).
(4, 5) Finally, in two trials comparing
cranberry products directly to prophylactic antibiotics, there was no
significant difference in infection rates in children with VUR given cefaclor
or children with a history of recurrent UTIs (VUR of any degree accepted) given
trimethoprim and those given cranberry, leading researchers to conclude that
cranberry juice was not inferior to either antibiotic in preventing UTIs.
In several studies, high dropout rates were
attributed to cranberry's tartness, though in one study, only one patient
(8.3%) in the cranberry group could not drink the juice because of the
tartness, a contrast from previous studies. Cranberry tablets may increase
excretion of oxalate and other lithogenic ions, a risk to those with
nephrolithiasis. Different products, doses, and dosing schedules used, and the
lack of data regarding PAC content except in one study, make specific
recommendations difficult.
Cranberry
products differ substantially. Quantifying PAC is achieved by several methods;
however, even the best method, dimethylaminocinnamaldehyde (DMAC), cannot
distinguish amounts or types of A-type PAC oligomers and is accurate only for
juice-based products, not those made from the cranberry skins or pomace.
American cranberry (V. macrocarpon) has
more PAC content than small cranberry (V.
oxycoccos) and should be used for UTI prevention. White cranberry contains
PAC precursors which do show anti-adhesion activity in vitro. Processing and
storage can alter PAC levels, yet in cranberry powders, extracts, tablets, and
capsules, labeled doses do not reflect PAC content.** In juice cocktails and
mixes, the percentage of juice does not reflect PAC content. Levels may vary in
different lots of juice from the same producer. No dosing studies have been
conducted in children, and optimal PAC doses are undefined in all populations. Pharmacokinetic
information is lacking except for limited studies of cranberry juice. Based on
the results of the eight clinical trials, cranberry juice, dosed from 2 to 5
mL/kg/day, showed the most benefit. In the absence of more definitive studies,
a minimum PAC dose of 36 mg/d in one daily dose or two 36-mg doses for acute
cases is suggested. [Note: The article incorrectly reported a dosage of 36
g/d.] Larger studies are needed.
—Mariann
Garner-Wizard
*However, during the first year of life, males
have more UTIs than females.
**Not all powders are whole cranberry. The cheaper
products are usually made from the dried skins or pomace after the juice is
removed. These are not soluble and cannot be measured accurately with
DMAC. These have delayed urinary anti-adhesion
activity which is stunted compared to the soluble juice-based powders in which
the PACs can be measured by DMAC. The juice powders are more expensive and act
more quickly, producing a more rapid anti-adhesion effect. The labels on
powdered cranberry supplements are currently not required to list if they are
juice or pomace-based, so consumers typically buy the cheaper, less-effective
products. Separate PAC quantification methods must be used for each product
type or the levels of PAC will not be reported correctly.
